How did I choose to become a scientist? To be honest, I wasn’t inspired by any major events, nor did I deeply contemplate this decision. Hard sciences like math and physics were just always easy for me. I grew up in Taiwan where the education system was very competitive with a lot of examinations all the time. From what I remember, I probably spent 1% of my effort in math, physics, and chemistry combined. Yet, it took 99% of my energy to memorize ten thousand years worth of Chinese history and literature. I remember staying up all night trying to memorize names of emperors, capitals of dynasties, major products of certain cities in China, the weather patterns of some cities in China, etc, etc, etc… so it was a no-brainer for me to choose science-related majors. For some reason I ended up in the department of food science in college. I never really got into learning how to make canned food, instant food, pickled food, and processed food. However, we also had to study microbiology and biochemistry. During my senior year in college, I chose an elective class with a very unusual title of “Molecular Biology/Genetic Engineering”. The instructor was a young professor who just received PhD and returned to Taiwan from MIT. He taught us how we could manipulate DNA, cutting them with enzymes and re-gluing them together with specific designs and orders. We could even put these newly-designed DNA into host cells and do all kinds of experiments with them to study biological functions. To me, this sounded like something that came out of science fiction stories, yet people were doing these experiments in that big country, the United States. Well, after that course, I decided that I was going to the big country to pursue Molecular Biology/Genetic Engineering for my graduate work.
In the particular graduate program I was in at the time, there were only two labs doing molecular biology work. It was not straightforward for me to get into a molecular biology lab. However, I did get into one of the two eventually and was able to perform my thesis work in molecular biology. I am grateful for the solid graduate education that I received, which laid the foundation for me to have a fantastic post-doctoral experience later on. For my graduate program, students were required to take two highly demanding laboratory courses in addition to standard courses in biochemistry, molecular biology, etc. These two lab courses include one for the biochemistry (all protein relevant lab work) and the other for molecular biology (all DNA and RNA relevant lab work). Because of these requirements, most students were well prepared for their thesis work in their chosen labs. My thesis mentor was very generous and always encouraged students to figure things out on their own before requesting his help. This mentoring style was critically important to my training because I was able to learn how to address questions myself when they arose. I also learned how to figure out different approaches in troubleshooting. All these skills were extremely valuable for my further training.
One of the most important decisions I have made for my science was choosing the human genetics field for my post-doctoral training. This decision allowed me to do science that is directly related to human well-being, which is extremely important to me personally. It motivates me because I know that everything I do in science is helping someone out there. Even if no one else knows about it, I know it.
My years of post-doctoral training were indeed a very exciting time. I had opportunities to do very exciting human diseases-related science. All my preparations during my Ph.D. became very useful at this time. It felt like I was at the right place at the right time with all the tools that I gathered previously to do the task at hand extremely well. Experiments worked easily for me, so I had a lot of productivity to show for that time.
I arrived at the lab where I did postdoc training (Baylor college of medicine at Houston) during a great time for doing human genetics positional cloning. I was fortunate to be part of the team that was positional cloning the Fragile-X syndrome gene. At the very end of the cloning process, an unexplainable observation was troubling us. We (the team) were pretty certain that the gene that we found was the right gene, but there was no obvious change in DNA even after several tries. I volunteered to do manual DNA sequencing since up to that point we were sequencing using an automatic sequencer machine. I still remember vividly the moment I developed the X-ray film and saw a pattern that looked like “repeat ladders”. The “repeat ladder” was the potential disease-causing change that we were looking for. After that, my study then naturally progressed to look at the repeat region itself. What is this “repeat ladder”? Why is it there and what does it mean? Does it do anything or it simply just sit there and does nothing? Does it have anything to do with causing Fragile-X and if yes, how? To find answers to these questions, I first figured out a way to examine this “repeat ladder” and did it for all the DNA samples that the lab had collected at that point. The results of the study were astonishing because it told us that the “repeat ladder” can expand and it can do this to an extensive level. And, it is the expansion of a simple “three letter codes” (repeat ladder) in the DNA that goes beyond normal size (number of repeats or number of steps on the ladder so to speak) that then causes the disease.
In addition to the amazing ability of the ladder to expand, the repeat number of the ladder (three codes) told us another unexpected finding. The number of the repeats (or the steps on the ladder) showed an interesting correlation with how early the patients started to show symptoms within each family that carry this disease. Previously, physician scientists have found that there is a group of diseases that have an intriguing phenomenon that they named “genetic anticipation.” The name came from the observation that disease symptoms begin to appear at an earlier age than the previous generation through each subsequent generation within a family, so one can anticipate the earlier appearance of the symptoms in the following generation. The results from my study showed that the numbers of repeat steps on the ladder get bigger through each generation within the same family. This exciting finding revealed to us that the expansion of the number of repeat steps in the ladder is likely the reason behind “genetic anticipation” that was observed for many years in this group of diseases. This finding suggested to me and my mentor (Dr. C. T. Caskey) that the expansion of similar repeat ladders are likely responsible for other diseases that also demonstrate “genetic anticipation.” We decided to try to prove whether this is indeed the case, and it just so happened that another lab in our institute in the building next to ours had been working on identifying the gene responsible for myotonic dystrophy for many years, and myotonic dystrophy is another disease with anticipation. We then collaborated with this lab to see if we could find the myotonic dystrophy gene for them by testing our hypothesis. In order to examine this concept, I decided to directly look for repetitive three codes DNA in the region where the gene should reside. At first, even though I had a rough idea of directly looking for three codes repetitive DNA, it still seemed overwhelming to sort through all of them, because there are 60 types of three code repeats!! And to look through the entire region which covers tens of millions of base pairs?! One night in the lab, I was sitting at my desk trying to figure out how to do this more efficiently, and it came to me suddenly that all I needed to do was to look for 6 types of repetitive codes which will cover all 60 different types (due to the nature of DNA sequence). I was so elated that I wished someone else were around so that I could share this fantastic new revelation!. After I realized this, we were able to find the three-code repeat in the expected myotonic dystrophy region very quickly (within few weeks) and proved that the expansions of three-code repeats are the molecular basis of genetic anticipation.
For unforeseeable reasons, I joined biotech start-up companies after post-doctoral training. In total, I spent about four and half years in biotech industry. I didn’t really learn anything significant with regards to science during this time, but I obtained some insight on how industry operates. For instance, industry research usually is more end-product orientated than purely satisfying scientific curiosity. In hindsight, I think that I joined the industry too early in my career so that the situation didn’t give me the freedom I needed to satisfy my scientific curiosity. Regardless, I was able to participate finding one of the genes responsible for premature aging and another one for early onset Alzheimer’s disease. After close to 5 years, I was ready to move into an environment where I could have more freedom in pursuing wider ranges of scientific investigation.
I started my academic career at University of Utah as a research associate professor. It was during this time that I began to do research on sleep, and I started an extremely productive career with my collaborators (Drs. Louis J. Ptacek and Chris Jones) in sleep science. After 5 years at Utah, I moved to University of California San Francisco where I continue the research in sleep science.